Functional Characterization of W147A: A High-Affinity Interleukin-11 Antagonist

Underhill-Day, Nicholas; McGovern, Lisa A.; Karpovich, Natalia; Mardon, Helen J.; Barton, Victoria A.; Heath, John K.

doi:10.1210/en.2002-0144

Cited by 37 publications

(31 citation statements)

References 60 publications

(75 reference statements)

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“…Second, the gp130 cytokine family as a whole should be considered as a single multifunctional entity whose signaling outputs are qualitatively and quantitatively dictated by the repertoire of receptors expressed by the responding cell type. These considerations highlight the use of receptor-specific agonists and antagonists in eliciting receptorspecific cell responses in both experimental (19) and therapeutic settings (22,32).…”

Section: Discussionmentioning

confidence: 99%

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Oncostatin M (OSM) Cytostasis of Breast Tumor Cells: Characterization of an OSM Receptor β–Specific Kernel

Underhill-Day

Heath

2006

Cancer Research

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The interleukin-6 cytokine oncostatin M (OSM) induces potent growth-inhibitory and morphogenic responses in several different tumor cell types, highlighting the importance of OSM signaling mechanisms as targets for therapeutic intervention. The specific molecular pathways involved are not well understood, as OSM can signal through two separate heterodimeric receptor complexes, glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR) A and gp130/OSM receptor B (OSMRB). In this investigation, we used a LIFR antagonist to help resolve signaling responses and identify patterns of gene expression elicited by the different receptor complexes. OSM-induced biological effects on breast tumorderived cell lines were specifically mediated through the gp130/OSMRB complex. Each cytokine tested exhibited differential signaling capability and manifested both shared and unique patterns of gene activation, emphasizing compositional differences in activator protein-1 transcription factor activity and expression. In particular, OSM strongly activated the c-Jun NH 2 -terminal kinase (JNK) serine/threonine kinase and downstream components, including activating transcription factor (ATF)/cyclic AMP-responsive element binding protein family member, ATF3. JNK/stress-activated protein kinase kinase inhibition abrogated cell morphogenesis induced by OSM, indicating an important role for this pathway in OSM specificity. These findings identify a core signaling/transcriptional mechanism specific to the OSMRB in breast tumor cells. (Cancer Res 2006; 66(22): 10891-901)

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Section: Discussionmentioning

confidence: 99%

“…OSM, LIF, and LIF-05 were expressed as glutathione S-transferase fusion proteins in Escherichia coli strain JM109. Expression, purification, and cleavage of proteins were carried out as described (21,22). Protein concentrations were determined using the Coomassie blue protein assay (Perbio Science UK Ltd., United Kingdom).…”

Section: Methodsmentioning

confidence: 99%

Oncostatin M (OSM) Cytostasis of Breast Tumor Cells: Characterization of an OSM Receptor β–Specific Kernel

Underhill-Day

Heath

2006

Cancer Research

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“…In mice, activation of the LIF receptor is required for blastocyst implantation, and IL-11R is required 1 day later for normal decidual response to the implanting blastocyst (3,4). Both receptors utilize gp130, and ligand binding can result in the activation of several members of the Stat family including Stat1, Stat3, and Stat5 through Jak kinases (9,26). Stat3 was selected as the specific target because treatment of LE from day 4 of pregnancy with LIF results in Stat3 phosphorylation, with no effect on Stat1 or Stat5, suggesting that Stat3 is the mediator of LIF's action on these cells (9).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Stat3 activation in the endometrium prevents implantation: A nonsteroidal approach to contraception

Catalano

Johnson

Campbell

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

110

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Activation of the receptors for leukemia inhibitory factor (LIF) and IL-11 is essential for embryo attachment and decidualization in mice. Both receptors induce activation of the Stat family of signal transducers via the Jak͞Stat pathway. Here, we aimed to establish whether activation of Stat3 in maternal endometrium is essential for successful implantation. Functional blockade of Stat3 before implantation, by injection into the uterine lumen of a cell-permeable Stat3 peptide inhibitor, reduced embryo implantation specifically by 70% (P < 0.001). Stat3 is phosphorylated in the luminal epithelium (LE) in response to LIF, and this phosphorylation was significantly reduced both in vitro and in vivo by the Stat3 inhibitor. The inhibitor also blocked induction by LIF of several LIF-regulated genes in the LE including Irg1, which has been shown previously to be essential for implantation. Successful implantation is therefore dependent on phosphorylation and activation of Stat3 in the endometrium before implantation. This finding provides a target for contraceptive development, based on selective blockade of signal transduction pathways essential for implantation. This study demonstrates that cell-permeable peptide inhibitors can be used effectively to target intracellular signaling pathways in the uterine LE.

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“…Protein expression, purification and 3C protease cleavage were performed as described previously (Hudson et al, 1996;Burgar et al, 2002;Underhill-Day et al, 2003). SDS-PAGE and subsequent staining with Coomassie Blue confirmed the purity of this protein.…”

Section: Cell Lysis Immunoprecipitation (Ip) and Western Blot Analymentioning

confidence: 99%

FRS2-dependent SRC activation is required for fibroblast growth factor receptor-induced phosphorylation of Sprouty and suppression of ERK activity

Brunton

Burgar

et al. 2004

Journal of Cell Science

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Activation of signalling by fibroblast growth factor receptor leads to phosphorylation of the signalling attenuator human Sprouty 2 (hSpry2) on residue Y55. This event requires the presence of the signalling adaptor fibroblast growth factor receptor substrate 2 (FRS2). The phosphorylation of hSpry2 is therefore mediated by an intermediate kinase. Using a SRC family kinase-specific inhibitor and mutant cells, we show that hSpry2 is a direct substrate for SRC family kinases, including SRC itself. Activation of SRC via fibroblast growth factor signalling is dependent upon FRS2 and fibroblast growth factor receptor kinase activity. SRC forms a complex with hSpry2 and this interaction is enhanced by hSpry2 phosphorylation. Phosphorylation of hSpry2 is required for hSpry2 to inhibit activation of the extracellular signalregulated kinase pathway. These results show that recruitment of SRC to FRS2 leads to activation of signal attenuation pathways.

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Functional Characterization of W147A: A High-Affinity Interleukin-11 Antagonist

Cited by 37 publications

References 60 publications

Oncostatin M (OSM) Cytostasis of Breast Tumor Cells: Characterization of an OSM Receptor β–Specific Kernel

Oncostatin M (OSM) Cytostasis of Breast Tumor Cells: Characterization of an OSM Receptor β–Specific Kernel

Inhibition of Stat3 activation in the endometrium prevents implantation: A nonsteroidal approach to contraception

FRS2-dependent SRC activation is required for fibroblast growth factor receptor-induced phosphorylation of Sprouty and suppression of ERK activity

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